Prolactin Inhibitor – Growth Hormone Suppressant in Acromegaly – Adjunctive Medication in Parkinson’s Disease
Action And Clinical Pharmacology: Bromocriptine is a dopaminomimetic ergot derivative with D2 type dopamine receptor agonist activity, which also has D1 dopamine receptor antagonist properties.
Bromocriptine inhibits the release and synthesis of prolactin by acting directly on the prolactin secreting cells of the anterior pituitary. In patients with acromegaly, in addition to lowering prolactin and elevated levels of growth hormone, bromocriptine has a beneficial effect on clinical symptoms and on glucose tolerance.
The dopaminomimetic activity of bromocriptine in the nigro-striatal pathway is considered responsible for the clinical benefits seen in patients with Parkinson’s disease.
The metabolism of dopamine, from exogenous and endogenous origin, is known to involve the formation of peroxides and free radicals. It has been postulated that these agents may in fact contribute to the progression of Parkinson’s disease by accelerating the rate at which neuronal cells are lost. Bromocriptine’s metabolic pathway does not involve the formation of such peroxides and free radicals. It has been suggested that because bromocriptine attenuates the timing and rate of levodopa dosage increase, early use of the drug may reduce risk of formation of potentially toxic peroxides and free radicals.
In man, bromocriptine is rapidly absorbed after oral administration with an absorption half-life of approximately 0.3 hours. The amount absorbed is about 65 to 95% of the oral dose. About 7% of the dose reaches the systemic circulation unchanged due to a high hepatic extraction rate and first pass metabolism. The plasma protein binding amounts to 96%. Bromocriptine is extensively metabolized by the liver. Only traces of the unchanged compound are found in urine, together with 2 major metabolites. Unchanged drug represents about 10 to 15% of peak levels of radioactivity in plasma measured after single dose of labelled drug. The active parent drug and the metabolites are primarily excreted via the liver, only 6% being eliminated via the kidney. In plasma, the elimination half-life was between 2 to 8 hours for the parent drug and 50 to 70 hours for the metabolites after single oral doses.
The extreme variability in gastrointestinal tract absorption and the extensive and individually variable first-pass metabolism are responsible for the broad variability in plasma concentrations of bromocriptine and, in part, for the variability in dose response.
Indications And Clinical Uses: Galactorrhea: with or without amenorrhea due to hyperprolactinemia.
Prolactin-dependent menstrual disorders and infertility: e.g., secondary amenorrhea, ovulatory insufficiency and short luteal phase.
Prolactin-secreting adenomas: As a treatment for inoperable macroadenomas or prior to surgery in order to facilitate removal, and as an alternative to surgery in patients with microadenomas.
Prolactin-dependent male hypogonadism.
Acromegaly: The first-line treatment of this condition is by surgery or radiotherapy. Bromocriptine may be a useful adjunct to such treatment, and can be used as monotherapy in special cases.
Parkinson’s disease: Bromocriptine is effective when used as adjunct therapy to levodopa in the symptomatic management of Parkinson’s disease. Used concomitantly with levodopa, bromocriptine facilitates the use of lower doses of levodopa in early disease and attenuates the rate of increase in the levodopa dosages on long-term usage. In this way the risk of long-term complications such as prominent dyskinesias and/or end-of-dose failure can be reduced.
Contra-Indications: Hypersensitivity to any of the components of bromocriptine, or other ergot alkaloids. Uncontrolled hypertension, hypertensive disorders of pregnancy (including eclampsia, pre-eclampsia or pregnancy-induced hypertension), hypertension post-partum and in the puerperium. Coronary artery disease and other severe cardiovascular conditions, symptoms and/or a history of serious psychic disorders. For procedure during pregnancy, see Pregnancy under Precautions. tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: In women with nonpuerperal galactorrhea, reduction of prolactin levels may lead to resumption of normal menses. Following discontinuation of medication, galactorrhea returns in some patients and leads to suspicion of pituitary adenomas; a complete investigation at specialized units to identify these patients is advisable.
Treatment with bromocriptine may effectively lower prolactin levels in patients with pituitary tumors but does not obviate the necessity for radiotherapy or surgical intervention where appropriate.
Long-term treatment (6 to 36 months) with bromocriptine in doses ranging from 20 to 100 mg/day has been associated with pulmonary infiltrates, pleural and pulmonary fibrosis, pleural effusion and thickening of the pleura in a few patients. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of bromocriptine should be contemplated. In those instances in which bromocriptine treatment was terminated, the changes slowly reverted toward normal.
In a few patients treated over years with bromocriptine at daily doses higher than 30 mg, retroperitoneal fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at an early reversible stage, it is recommended that its manifestations (e.g., back pain, edema of the lower limbs or impaired kidney function) should be watched in this category of patients. Bromocriptine medication should be withdrawn immediately if fibrotic changes in the retroperitoneum are diagnosed or suspected.
Particular attention should be paid to patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure, e.g., vasoconstrictors such as sympathomimetics or ergot alkaloids including ergometrine or methylergometrine. Although there is no conclusive evidence of an interaction between bromocriptine and these drugs, their concomitant use in the puerperium is not recommended.
Precautions: Bromocriptine may cause hypotension, primarily postural; periodic monitoring of the blood pressure, particularly during the first days of therapy, is advisable.
Occupational Hazards: In some patients, dizziness (vertigo) may occur with bromocriptine; patients should therefore be cautioned against activities requiring rapid and precise responses such as driving an automobile or operating dangerous machinery until their response has been determined.
Care should be exercised when administering bromocriptine concomitantly with phenothiazines or with other medications known to lower blood pressure. Dosage should be adjusted accordingly.
In some patients the concomitant use of bromocriptine and alcohol has given rise to alcohol intolerance and the tolerability to bromocriptine may be reduced by alcohol.
In patients being treated with bromocriptine for galactorrhea, prolactin induced amenorrhea, menstrual disorders or acromegaly, infertility might be reversed by restoration of normal menses and ovulation. Women who do not wish to conceive should, therefore, use a reliable method of contraception. Since pregnancy may occur prior to initiation of menses it is recommended that a pregnancy test be conducted at least every 4 weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period.
A few cases of gastrointestinal bleeding and gastric ulcer have been reported. If this occurs, bromocriptine should be withdrawn. Patients with a history or evidence of peptic ulceration should be closely monitored when receiving the treatment.
In rare cases, serious adverse events including hypertension, myocardial infarction, seizures and strokes, or psychic disorders have been reported in postpartum women treated with bromocriptine for the inhibition of lactation. In some patients the development of seizures or strokes was preceded by severe headache and/or visual disturbances. Causal relationship of these events to the drug is uncertain.
The use of bromocriptine in the routine inhibition of physiological lactation is not recommended. When the drug is used for the treatment of other conditions, periodic monitoring of blood pressure is advisable. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbances) or evidence of CNS toxicity develop, the administration of bromocriptine should be discontinued and the patient should be evaluated promptly.
Safety and efficacy of bromocriptine have not been established in patients with severe renal or hepatic disease.
Bromocriptine therapy has been demonstrated to be effective in the short-term management of amenorrhea/galactorrhea. Data are not available on the safety or effectiveness of its use in long-term continuous dosage in this indication or in patients given repeated courses of treatment following recurrence of amenorrhea/galactorrhea after initial treatment. Recurrence rates are reportedly very high, ranging from 70 to 80%.
Bromocriptine should always be taken with food. In cases where adverse effects, such as nausea, vomiting and vertigo are severe or persistent, the therapeutic dosage of bromocriptine should be reduced to half of 1 tablet daily (1.25 mg) and increased gradually to that recommended. The dopamine antagonist domperidone may be useful in the control of severe gastrointestinal side effects in Parkinsonian patients receiving bromocriptine (see Drug Interactions).
As with all medication, bromocriptine should be kept safely out of the reach of children.
Prolactin Secreting Adenoma Patients: Since patients with macro-adenomas of the pituitary might have accompanying hypopituitarism due to compression or destruction of pituitary tissue, one should make a complete evaluation of pituitary functions and institute appropriate substitution therapy prior to administration of bromocriptine. In patients with secondary adrenal insufficiency, substitution with corticosteroids is essential. The evolution of tumor size in patients with pituitary macro-adenomas should be carefully monitored and, if evidence of tumor expansion develops, surgical procedures must be considered.
If, in adenoma patients, pregnancy occurs after the administration of bromocriptine, careful observation is mandatory. Prolactin-secreting adenomas may expand during pregnancy. In these patients, treatment with bromocriptine often results in tumor shrinkage and rapid improvement of the visual field defects. In severe cases, compression of the optic or other cranial nerves may necessitate emergency pituitary surgery.
Pregnancy : In patients receiving bromocriptine, immunological confirmation of suspected conception should be performed as soon as possible and bromocriptine treatment stopped unless, in the opinion of the treating physician, the possible benefit to the patient outweighs the potential risk to the fetus. In any event, the patient must be monitored closely throughout pregnancy for signs and symptoms which may develop if a previously undetected prolactin-secreting tumor enlarges.
In human studies with bromocriptine, there were 1 410 reported pregnancies, which yielded 1 236 live and 5 stillborn infants from women who took bromocriptine during early pregnancy. Among the 1 241 infants, 43 cases (31 minor and 12 major) of congenital anomalies were reported. The incidence (3.46%) and type of congenital malformations and the incidence of spontaneous abortions (11.13%) in this group of pregnancies do not exceed that generally reported for such occurrences in the population at large.
Patients with pronounced enlargement of the sella turcica or a visual field defect should, in the first instance, be treated by surgery and/or radiotherapy. If pregnancy occurs in the presence of a pituitary microadenoma, close supervision throughout pregnancy is essential. This includes regular checking of the visual fields.
Lactation : Since bromocriptine inhibits lactation, it should not be administered to mothers who elect to breast-feed.
Parkinson’s Disease: Use of bromocriptine, particularly in high doses, may be associated with mental confusion and mental disturbances. Since patients with Parkinson’s disease may manifest varying degrees of dementia, caution should be exercised when treating such patients with bromocriptine.
Bromocriptine administered alone or concomitantly with levodopa may cause visual or auditory hallucinations. These usually resolve with dosage reduction but discontinuation of bromocriptine may be required in some cases. Rarely, after high doses, hallucinations have persisted for several weeks following discontinuation of bromocriptine. Caution should be exercised when administering bromocriptine to patients with a history of myocardial infarction, particularly if they have a residual atrial, nodal or ventricular arrhythmia.
Symptomatic hypotension can occur and, therefore, caution should be exercised when administering bromocriptine, particularly in patients receiving antihypertensive medication. Periodic evaluation of hepatic, hematopoietic, cardiovascular and renal function is recommended.
Drug Interactions: The concomitant use of erythromycin, josamycin, other macreolide antibiotics or octreotide may increase bromocriptine plasma levels.
Domperidone, a peripheral dopamine antagonist, may cause increases in serum prolactin. In so doing, domperidone may antagonize the therapeutically relevant prolactin-lowering effect of bromocriptine. It is possible that the anti-tumorigenic effect of bromocriptine in patients with prolactinomas may be partially blocked by domperidone administration.
Adverse Reactions: The most frequently observed adverse reactions are nausea, vomiting, headache and gastrointestinal side effects such as abdominal pain, diarrhea and constipation. All these effects may be minimized or even prevented by giving small initial doses of bromocriptine and by taking it with food.
Postural hypotension can, on rare occasions, lead to fainting, and “shock-like” syndromes have been reported in sensitive patients. This is most likely to occur during the first few days of bromocriptine treatment.
In clinical studies to date, the following adverse events were noted: In postpartum women treated with bromocriptine, some rare serious adverse events (about 1 in 100 000) have been reported. These include hypertension, visual disturbances, myocardial infarction, seizures and strokes, or psychic disorders. In some patients the occurrence of seizures or strokes was preceded by severe headache and/or visual disturbances. Causal relationship of these events to the drug is uncertain.
Amenorrhea/Galactorrhea/Female Infertility/Acromegaly: The incidence of side effects in these indications is 68%, and are generally mild to moderate in degree. Therapy was discontinued in approximately 6% of patients because of adverse effects. In decreasing order of frequency these are: nausea 51%, headache 18%, dizziness 16%, fatigue 8%, abdominal cramps 7%, lightheadedness 6%, vomiting 5%, nasal congestion 5%, constipation 3% and diarrhea 3%.
Parkinson’s Disease: When bromocriptine is added to levodopa therapy, the incidence of adverse reactions may increase. The most common newly appearing adverse reactions in combination therapy with levodopa are: nausea, abnormal involuntary movements, hallucinations, confusion, “on-off” phenomenon, dizziness, drowsiness, faintness, fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation and vertigo.
General: Less common adverse reactions include: anorexia, anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizures, fatigue, headache, lethargia, mottling of skin, nasal congestion, nervousness, nightmares, paresthesia, skin rash, hair loss, changes in urinary frequency, urinary incontinence and urinary retention. Usually, these side effects are dose dependent and can be controlled by a reduction in dosage. Rarely signs or symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud’s syndrome may occur.
Abnormalities in laboratory tests may include elevation of blood urea nitrogen, AST, ALT, GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical significance.
The occurrence of adverse reactions may be lessened by temporarily reducing dosage to 1.25 mg 2 or 3 times daily.
Symptoms And Treatment Of Overdose: Symptoms: There have been several reports of acute overdosage with bromocriptine in children and adults. All patients who have taken an overdosage of bromocriptine alone have survived; the maximum single dose so far ingested is 325 mg. Symptoms reported could have resulted from over-stimulation of dopaminergic receptors; they included nausea, vomiting, dizziness, drowsiness, hypotension and hallucinations. tag_Treatment
Treatment: The management of acute intoxication is largely symptomatic. The cardiovascular system should be monitored. Metoclopramide can be used to antagonize the emesis and hallucinations in patients who have taken high doses.
Dosage And Administration: Bromocriptine should always be taken with food. In order to establish tolerance, the first dose of 1.25 to 2.5 mg (1/2 to 1 tablet), depending on the indication, should be given at bedtime with food. Please consult the detailed dosage recommendations for each indication.
Galactorrhea with or without amenorrhea due to hyperprolactinemia: 1.25 to 2.5 mg (1/2 to 1 tablet) at bedtime with food to establish tolerance; gradually increase after 2 to 3 days to 2.5 mg twice daily with meals. If required the dose may be increased to 2.5 mg 3 times daily. Continue treatment until milk secretion has ceased completely or, in the case of menstrual dysfunction, until the menstrual cycle has returned to normal.
Prolactin-dependent menstrual disorders and infertility: 1.25 to 2.5 mg (1/2 to 1 tablet) at bedtime with food to establish tolerance. Gradually increase after 2 to 3 days to 1 tablet twice daily with meals. If required, the dose may be increased to 2.5 mg 3 times daily.
Prolactin-secreting adenomas: 1.25 mg (1/2 tablet) 2 or 3 times daily, increasing gradually (average maintenance dose: 5 to 7.5 mg daily). If necessary to keep plasma prolactin adequately suppressed, dosage may be increased gradually over a period of several weeks to 10 to 20 mg daily (4 to 8 tablets or 2 to 4 capsules) with meals.
Hyperprolactinemia in men: 1.25 to 2.5 mg (1/2 to 1 tablet) at bedtime to establish tolerance. Gradually increase after 2 to 3 days to 2.5 mg twice daily with meals or more, as required, to 2.5 mg 3 times/day with meals.
Acromegaly: 1.25 to 2.5 mg (1/2 to 1 tablet) at bedtime with food to establish tolerance, increasing gradually over a period of 2 to 4 weeks to 10 to 20 mg (4 to 8 tablets or 2 to 4 capsules) daily with meals, depending on clinical response. Daily requirements of 20 mg should be taken in 4 equally divided doses.
For convenience and after titration, some patients may use the 5 mg capsules for maintenance therapy.
The maximum recommended daily dose is 20 mg [8 (2.5 mg) tablets or 4 (5 mg) capsules]. In the event of serious or persistent adverse effects, the dosage should be reduced to 1.25 mg (1/2 tablet) and increased again gradually to the recommended dose. If reactions such as nausea, vomiting, vertigo or headaches continue to be severe, bromocriptine should be discontinued.
Parkinson’s Disease: Bromocriptine should be added to levodopa therapy. It is desirable to combine a slow increase of bromocriptine with a concomitant, limited and gradual reduction of levodopa.
Bromocriptine dosage should be individualized. The initial dose is 1.25 mg (1/2 tablet) at bedtime to establish tolerance. Thereafter, the recommended dosage is 2.5 mg daily in 2 divided doses, with meals. The dosage may be increased, if necessary, by adding an additional 2.5 mg/day, once every 2 to 4 weeks, taken in 2 or 3 divided doses with meals.
The maximum recommended daily dosage is 40 mg. Clinical assessments are recommended during dosage titration to ensure that the lowest effective dose is employed. Where dose levels permit, use of the 5 mg capsule may be found more convenient by many patients.
Availability And Storage: Tablets: Each easy-to-break white, oval-shaped tablet with parting facilitated score line, upper is sloped face and embossed with double heads, bisect, double heads, with lower flat and embossed “PARLODEL”, contains: bromocriptine mesylate 2.87 mg corresponding to bromocriptine base 2.5 mg. Nonmedicinal ingredients: cornstarch, edetate disodium, lactose and maleic acid. Bottles of 100.
Capsules: Each caramel and white, size 3, hard shell capsule, spin printed in black “PARLODEL 5 mg” on the cap with 2 heads, one inside the other, on the body, contains: bromocriptine mesylate 5.74 mg corresponding to bromocriptine base 5 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, lactose, magnesium stearate and maleic acid. Bottles of 100.
Protect from light and store between 15 and 25Â°C. (Shown in Product Recognition Section)
PARLODELÂ® Novartis Pharmaceuticals Bromocriptine Mesylate Prolactin Inhibitor – Growth Hormone Suppressant in Acromegaly – Adjunctive Medication in Parkinson’s Disease
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